Process for the preparation of 9alpha-halogeno-11beta-substituted steroids



United States Patent M US. 'Cl. 260-349 15 Claims ABSTRACT OF THE DISCLOSURE A process for introducing nucleophilic anions into the llfi-position of steroids comprises reacting a 900- halogeno-ll/i-X-steroid, X being a leaving group (preferably a halogeno or sulfonyloxy radical), with a nucleophile, YZ, Y being a strong nucleophilic anion (preferably anion (preferably hydroxyl, azide or halide) and Z being a cation, whereby is effected replacement of said llB-X group by said anion, Y, and there is formed a 90:- halogeno-llB-Y-steroid. Preferred embodiments of this process are those wherein the nucleophilic reagent, YZ, is water and the llfi-X leaving group is either llfl chloroor llfl-tosyloxywhereby are obtained 9a-halogeno-11fihydroxy-steroids. This process is useful for preparing new classes of compounds, e.g. 9a-halogenoll 8-azido steroids, and in preparing known, pharmacologically active steroids, e.g. hydrocortisone and prednisolone.

This invention relates to a novel process and to novel compounds produced thereby.

The invention sought to be patented is described as residing in the concept of reacting a 9a-halogeno-l1B-X- steroid selected from the group consisting of the androstane and pregnane series and the 19-nor analogs thereof wherein X is a leaving group, and preferably is halogeno or a sulfonyloxy radical, X being other than iodo when said 9a-halogeno is 9a-iodo; with a reagent, YZ, wherein Y is a strong nucleophilic anion such as hydroxyl, azide, halide, and equivalents thereof; whereby is elfected replacement of said llB-X group by said anion, Y, and there is formed a 9a-halogeno-l 1,8-Y-steroid of the androstane and pregnane series and the 19-nor analogs thereof.

The reagents, YZ, necessary to our process are ionizable compounds known in the art as nucleophiles (i.e. nucleusloving groups seeking electron-deficient centers) having a nucleophilic anion, Y (preferably hydroxyl, azide, and halide), and a cation, Z Qpreferably hydrogen, ammonium, and alkali earth and alkaline earth metal ions). The ionizable reagents, YZ, include compounds which are ionized and unionized per se, the per se unionized reagents being ionizable in the sense that they act as donors for the anion, Y, under the conditions of our process. The preferred reagents are those possessing the anions hydroxyl, azide, and halide.

Considered as equivalents of the foregoing preferred nucleophilic anions, are anions Y, such as cyanide, lower alkoxy, phosphate, amino, lower alkylamino, arylamino, lower alkanoyloxy, arylcarboxy, thio, thio-lower alkyl, thioaryl and the like. According to our invention, each of the foregoing anions, Y, when reacted with a 90:,115- dihalogeno-steroid or a 9a-halogeno-llp-sulfonyloxysteroid under the conditions of our process will replace the halogeno or sulfonyloxy group at C-ll to form a 900- halogeno-l 1 fl-Y-steroid.

Typical reagents, YZ, which are per se unionized include water (Y=hydroxy), lower alkanoic acids and in particular acetic acid (Y=alkanoyloxy, e.g. acetoxy), arylcarboxylic acids such as benzoic (Y=benzoyloxy) and 3,463,793 Patented Aug. 26, 1969 toluic (Y=toluyloxy) acids, hydrogen sulfide (Y=thiol), alkyl-mercaptans such as methanethiol (Y=thiomethane); arylmercaptans such as benzenethiol (Y=thiophenyl), ammonia (Y=amino); alkyl and aryl amines such as methylamine (Y=methylamino), dimethylamine (Y: dimethylamine), phenylamine (Y=phenylamino); and the like. Typical per se ionized nucleophilic reagents include sodium azide (Y'=azide), sodium chloride (Y=chloride), sodium bromide (Y=bromide), potassium cyanide (Y= cyanide), sodium methylate (Y=methoxy), alkali metal hydrosulfides such as sodium hydrosulfide (Y=thiol), alkali metal phosphates (Y=phosphate), and the like.

By terms such as lower alkyl, lower alkoxy, lower alkanoyloxy are meant radicals wherein the hydrocarbon residue has preferably up to 8 carbon atoms.

By a leaving group is meant a group capable of leaving a bonded site when in the presence of a strong nucleophilic anion. We have discovered, for example, that when 9a,1113-dichloro-l6ot-methyl-1,4-pregnadiene- 17u,21-diol-3,20-di0ne 21-disodium phosphate or 9achloro-l 1fi-para-toluene-sulfonyloxy-16a-methyl-1,4-pregnadiene-l7a,21-diol-3,20-dione ZI-disodium phosphate is dissolved in water, the llli-chloro (or the llB-tosyloxy) group leaves the steroid nucleus and is replaced at C-ll by hydroxyl with formation of 9u-chloro-16a-methyl-prednisolone 21-s0diurn phosphate, a potent anti-inflammatory agent.

Contemplated as equivalents to the preferred halogeno and sulfonyloxy leaving groups (X) are moieties such as those set forth by Cram and Hammond, Orangic Chemistry, 2nd edition, p. 274 (Table 14.2), McGraw-Hill Inc., New York, 1964, including substituted-carboxy, sulfate, chlorosulfite, chlorophosphite, and the like.

The halogens contemplated as leaving groups (i.e. X) at 0-11 include fluorine, chlorine, bromine and iodine.

Included within the term a sulfonyloxy radical, defining a class of preferred leaving groups (X) at C-l1, are hydrocarbonsulfonyloxy radicals having up to 20 carbon atoms including alkylsulfonyloxy radicals (e.g. methylsulfonyloxy) (i.e. mesyloxy), ethylsulfonyloxy; arylsulfonyloxy radicals (e.g. benzenesulfonyloxy and naphthalene-B-sulfonyloxy); alkarylsulfonyloxy radicals (e.g. para-toluenesulfonyloxy) (i.e. tosyloxy), ortho-toluenesulfonyloxy, meta toluene sulfonyloxy, 3,4 xylenesulfonyloxy and dodecylbenzenesulfonyloxy. Other sulfonyloxy radicals contemplated at C-ll are substituted hydrocarbonsulfonyloxy radicals having up to 20 carbon atoms exemplified by p-bromobenzenesulfonyloxy, pchlorobenzenesulfonyloxy, m chlorobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, p-methoxybenzenesulfonyloxy, o-dimethylaminobenzenesulfonyloxy, m (or p)-cyano benzenesulfonyloxy, and the like.

Our process is usually carried out in solution in a polar solvent which is preferably a hydroxylic solvent. By hydroxylic solvent is meant a solvent containing a hydroxyl function, including water (which thus may serve a dual role both as solvent and as reagent, YZ), lower alkanols (preferably methanol), phenols, and hydrocarbon carboxylic acids, preferably lower alkanoic acids such as acetic and propionic acids, and mixtures of the foregoing.

Preferred embodiments of our process are those wherein the nucleophilic reagent, YZ, is water (the nucleophilic anion (Y) being hydroxyl, and the cation (Z) being hydrogen), and wherein the 11 3-X leaving group is either llfl-chloro or llli-tosyloxy (i.e. llfi-p-toluenesulfonyloxy), whereby are obtained 9a-ha1ogeno-11p-hydroxysteroids of the androstane and pregnane series and the 19- nor analogs thereof. The preferred embodiment of our process finds its greatest usefulness when the 904-112110- geno-llfl-chloro (or tosyloxy)-starting steroid is a pregnane having a cortical side chain esterified at C21, said ester being preferably a 21-phosphate alkali metal salt when the starting steroid is a 9a,11fl-dihalogeno-2l-hydroxypregnane, and being preferably a 21-lower alkanoate when 9a-halogeno-11,B-tosyloxy-Zl-hydroxy-pregnanes are utilized as starting compounds. Reaction of each of the foregoing with water yields 9a-halogeno-l1fi-hydroxypregnanes having the cortical side chain esterified at C-2l by phosphate alkali metal salts or lower alkanoate, respectively, which are a known class of compounds possessing adrenocortical activity (eg as in hydrocortisone, prednisolone, and the like which are well-known antiinflammatory agents).

In general, when carrying out our process, a solution of the 9u-halogeno-1lfi-X-steroid (X being preferably chloro or tosyloxy) together with the nucleophilic reagent, YZ (the anions, Y, being preferably hydroxy], azide, and halide) are stirred together at moderate temperatures (usually in the range of about 3075 C.) until the reaction is completed as evidenced by chromatographic analysis (to determine the absence of starting material), analysis for the presence of an equivalent of the leaving group (eg when X is chloro, analysis for chloride ion), as well as other techniques well-known in the art. Isolation of the resulting 9a-halogeno-llfi-Y-steroid is then effected according to procedures well-known in the art. Greater yields of substitution products are obtained in shorter periods of time by our process when large molar excess of nucleophilic reagent per mole of 9ot-halogeno-steroid are used. Additionally, to minimize undesirable competing side reactions, the pH of the reaction solution is maintained usually in the range of from pH 4 to about pH 8.5 and preferably in the range of from about pH 6 to about pH 7.5.

Thus, in a preferred mode of this invention, 9a,11;3-dichloro 16a-methyl-l,4-pregnadiene-l7a,2l-diol-3,20-dione 21-disodium phosphate (X is chloro) in water is stirred at 60 C. for about 6 hours during which time the pH falls from about 8.5 to less than 6, as the nucleophile (i.e. Y=hydroxy) enters at C-11 with liberation of chloride (X) ion. The resulting halohydrin (i.e. the 9:1- chloro-llfi-hydroxy-derivative) is isolated by acidifying the reaction mixture to a pH of less than 1 followed by filtration of the resulting precipitate of 9ot-chloro-1l6- hydroxy 16cc methyl-1,4-pregnadiene-17a,21-dio1-3,20- dione 2l-phosphate (a known anti-inflammatory agent). In turn the 21-phosphate may be subjected to enzymatic dephosphorylation according to known procedures to obtain the parent alcohol, 9ot-chloro-16u-methylprednisolone, also a potent anti-inflammatory agent.

In the above reaction the formation of hydrogen chloride resulting from the liberated llfi-chloro-group and cation Z, causes conversion of the disodium phosphate ester to mono sodium ester. Further acidification with strong acid liberates the 21-phosphate ester.

In general, when the starting steroid is a 9a,11B-dihalogeno-Zl-oxygenated pregnane and it is desired to prepare a 9a-halogeno-1lfl-hydroxy-pregnane, the 2l-phosphate alkali metal salt (e.g. mono or disodium phosphate) is preferred since it renders the steroidal substrate soluble in water and also appears to facilitate the ease with which the leaving group (X) undergoes reaction as measured by the speed of reaction, thus shortening the time necessary to effect complete conversion of the 9a,1lB-dihalogenosteroid to a 9a-halogeno-1lfi-hydroxy-steroid. Under the conditions set set forth above, the reaction time necessary to convert an llfi-chloro group to an llfi-hydroxyl function in a 9a,l1B-dichloro-4-pregnene-17a,21-diol-3,20 dione 21-disodium phosphate is usually from about 3 to hours.

When the free steroidal alcohol or a 21-lower alkanoate or a 21-alkoxycarboxylate thereof is used as starting steroid in the above reaction, a lower alkanol, preferably methanol, is advantageously used as solvent or co-solvent. Thus, when 9a,1lB-dichloro-l6ot-methyl-1,4-pregnadiene- 3,20-dione 21-acetate dissolved in 50% aqueous methanol is stirred at 60 C. for 24 hours, there is obtained the corresponding chloro llfl-hydroxy-l6a-methyl-1,4- pregnadiene-17;1-diol3,20-dione 2l-acetate in admixture with some of the corresponding 21-hydroxy derivative. The latter compound is formed via hydrolysis of the 21-lower alkanoate by the action of hydrogen chloride formed from the liberated llfl-chloro group and the cation (hydrogen). The mixture of products is easily converted to either the 2l-ester alone via reaction with acetic anhydride in pyridine, or to the 21-hydroxy compound by hydrolysis with acid or base by techniques well known in the art.

It is apparent thta in the above reaction, when other halogeno groups are present at C-9 of the starting 9,11- dihalogeno steroids, such as in 90t-bI'OII10-1ll3-ChlOIO-160tmethyl-1,4-pregnadiene-3,20-dione 21-disodium phosphate and in 9ot-fiuoro-l1,8-chloro-1,4-pregnadiene-17a,21-diol- 3,20-dione 21-disodium phosphate, reaction thereof with water at 60 C. according to our process, will yield the corresponding halohydrin, e.g. 9ot-bromo-l1B-hydroxy- 16a methyl-1,4-pregnadiene-17a-21-diol-3,20-dione 21- sodium phosphate, both of which possess strong glucocorticoid activity.

We have described hereinabove a preferred mode of our process wherein a 9ot,1l 3-dihalogeno-2l-oxygenated pregnane upon treatment with water is converted to the corresponding 9a-halogeno-1lfl-hydroxy-derivative. An other preferred embodiment of our process involves replacement of an 11 B-sulfonyloxy, preferably an llfi-paratoluenesulfonyloxy (i.e. tosyloxy) group by a hydroxyl group. For example, 9a-chloro-11/8-tosyloxy-16a-methyl- 1,4 pregnadiene 17a,21 diol 3,20 dione 2lcathylate dissolved in 50% aqueous methanol is stirred for about 21 hours at 60 C. The resulting 9,11-halohydrin, i.e. 90c chloro 11B hydroxy 16a methyl 1,4 pregnadiene-17et,21-diol-3,20-dione 2l-cathylate is then conveniently isolated by distilling the methanol followed by extraction of the reaction mixture with a waterimmiscible solvent (e.g. methylene chloride) followed by concentration of the combined extracts to yield the 21- cathylate of the aforenamed 9u-chloro-11fi-hydroxypregnadiene.

The use in our process of an ll s-p-toluenesulfonyloxy as a leaving group is particularly advantageous when it is desired to introduce groups at C1l other thanhydroxyl. For example, when 9a-chl0r0-l1,6-tosyloxy-16wmethyl- 1,4 pregnadiene l7a,21 diol 3,20 dione 2l-acetate (i.e. 9a-chloro-l6a-methylprednisolone ll-tosylate 21- acetate) is added to a saturated solution of sodium azide in aqueous methanol (e.g. 1:4 water/methanol) (said solution having been titrated to about pH 6 with acetic acid), and said reaction solution is stirred at about 60 C. for about 24 hours, the llB-tosyloxy grOup (X) is replaced by the nucleophilic azide anion (Y) with concomitant formation of p-toluenesulfonic acid, and there is formed 911- chloro-l1,8-azido-16a-methyl-1,4-pregnadiene-l7a,2l-diol-3,20-dione, a member of a novel class of compounds, possessing anti-inflammatory activity as described and claimed in US. application Ser. No. 638,606 filed May 15, 1967.

We have found when carrying out our process utilizing per se ionized nucleophilic reagents which form strongly basic solutions, such as sodium azide, potassium cyanide and sodium methylate, that it is advantageous to buffer the solutions thereof to a pH in the range of from about 4 to about 7.5 prior to addition of the 9a,11B-dihalogenoor 9ot-halogeno-llfl-chlorosteroid in order to minimize undesirable side reactions such as that between halogeno groups and strong bases.

We have also found that, in general, our process proceeds at a faster rate when carried out in the presence of water. Thus, when replacing the llfl-halogeno or an llfi-tosyloxy group at Cll with an azide, it is advantageous to utilize aqueous methanol as solvent rather than anhydrous methanol.

With the presence of water in the reaction mixture, in addition to effecting replacement of the llfi-halogeno or llfi-tosyloxy group by azide, there is also formed some llfi-hydroxy steroid which is easily separated from the resulting 11fl-azido-derivative via chromatographic techniques.

Similarly, when replacing an 11/3-tosyloxy group with a halide by reaction with sodium chloride or sodium bromide, our process is best carried out in aqueous methanol. 9a-Ch0l01 11B tosyloxy 16a-rnethyl-l,4- pregnadiene l7a,21-di0l-3,20-dione 2l-cathylate when stirred at 60 C. in a solution of sodium chloride (or sodium bromide) in aqueous methanol affords replacement of the llfl-tosyloxy leaving group by the nucleophilic halide ion to obtain 9u,1lp-dichloro-l6ot-methyl- 1,4 pregnadiene 17oc,21-diOl-3,20-di0116 21-cathylate (or 9a chloro 115 bromo 16oz methyl-1,4-pregnadiene l7u,2l-diol-3,20-dione 2l-cathylate when sodium bromide is the nucleophilic reagent used).

It is to be noted that in our process the leaving group X may be halogeno and, at the same time the nucleophilic anion may be a halide anion. Thus, for example, 904,115- dibromo 1,4 pregnadiene 17a,21-diol-3,20-dione 21- acetate upon reaction with a saturated solution of sodium chloride in aqueous methanol (1:4) according to our process will yield 9a-brom0-1lfi-chloro-1,4-pregnadienel7u,2l-diol-3,20-dione 2l-acetate.

By our novel process it is thus now possible to replace the substituent, X, at C-11 of a 9a,11,8-dihalogenosteroid or a 9a-halogeno-llfi-sulfonyloxy-steroid with a nucleophilic anion, Y (preferably hydroxy, halogeno and azido) with retention of the respective spatial configurations at C-9 and C1 1, and thereby obtain a 9a-halogeno- 11/3-Y-steroid. In essence, therefore, the embodiment of our novel process represents a nucleophilic substitution reaction at a saturated carbon atom on a steroidal substrate, with the 11/3-X group (e.g. halogeno or sulfonyloxy) being the leaving group, and the 9a-halogeno- (preferably 9oc-ChlOtO-) acting as a neighboring group, with the nucleophilic anions, Y (preferably hydroxyl, azide and chloride) entering with formation of the corresponding 9a-halogeno-l1,6-Ysteroid. It is advantageous that our process produces a 9a-halogen0-1lfl-nucleophilic substitution steroidal product having the same spatial configuration as the starting 9a-halogeno-1lli-halogeno (or sulfonyloxy)-ster0id since in the steroid art, and particularly in the adrenocorticoid pregnane series, it is necessary to maintain the 9a-halogeno-11fl-Y configuration to maintain pharmacological activity, particularly when Y is hydroxy, since the 9ot-halogeno-11fl-hydroxypregnanes having the cortical side chain at C-l7 are, in general active as corticoids, whereas the inverse spatial isomers thereof, i.e. the lla-hydroxy derivatives are, in general, inactive as corticoids.

In addition to the foregoing, our process provides a convenient method of preparing 2l-phosphate esters and salts thereof of 9a-halogeno-llfi-hydroxy-pregnanes having the Cl7 cortical side chain. This is of particular value when it is desired to prepare the 21-phosphate of a 9achloro-l lfi-hydroxyor a 9a-bromo-1lfi-hydroxypregnane such as 9a-chloro-1fiwmethylprednisolone or 9a-bromol6a-methylprednisolone which are difficult to prepare via procedures now known in the art.

In general, without affecting the course of our process {i.e. the replacement at 0-11 of a sulfonyloxy or a halogeno group by a nucleophilic anion such as hydroxyl, azide and halide), the starting 9ot-halogeno-1lfi-halogeno (or substituted sulfonyloxy)-pregnane or androstane or 19-nor analog thereof may have double bonds present in the steroidal nucleus such as at C-1 and C-4, C-6, C7, C-8, C-14, 0-15 and (I-16; methyl, methylene, and hydroxyl substituents and derivatives thereof (e.g. esters and others) such as at C4, C-4, C-5, C-6, C-7, C-14 and C-16; fluoro and chloro such as at C-6 and C-16; and keto groups such as at C-3 and C-16. It is understood that our process may be carried out on any halogeno-llfl-halogeno- (or sulfonyloxy) steroid and utilizing, in addition to the preferred nucleophilic anions, equivalents thereof as set forth hereinabove, and there well be prepared the corresponding 9a-halogeno-11p-Y- steroid.

Thus, 9a-chloro-11 3-tosyloXy-16ot-rnethyl-1,4-pregnadiene-17a,21-diol-3,20-dione 21-acetate in an aqueous methanol solution when stirred at 60 C. with a nucleophile such as potassium cyanide, sodium, methylate, phosphoric acid, ammonia, methyl amine, phenyl amine, acetic acid, benzoic acid, hydrogen sulfide, methyl mercaptan or phenyl mercaptan will cause replacement of the 11fltosyloxy group by the nucleophilic anion Y with formation of the corresponding 9u-halogeno-1lfl-Y-steroid, e.g.

9a-chloro-1lfi-cyano-16a-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 21-acetate 9a-chloro-1 1B-methoxy-loot-methyl-l,4-pregnadiene 17a,21-diol-3,20-dione 21-acetatc 9a-chloro-l lfi-phosphoryloxy-16u-methyl-1,4-pregnadiene-17ml1-diol-3,20dione 21-acetate 9ot-chloro-l 1 fl-amino-16ot-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 21-acetate 9a-chloro-1 1 fl-methylamino-l 6u-methy1-1,4-pregnadiene- 1706,21-dl0l-3,20-dl0fl 2l-acetate 9a-chloro-l 1 B-phenylamino- 1 6a-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione ZI-acetate 9ot-chloro-1 1,S-acetoxy-16ot-methyl-1,4-pregnadienel7ot,2l-diol-3,20-dione 2l-acetate 9 a-ChlOI'O-l lB-benzoyloxyd 6a-methyl-1,4-pregnadiene- 17u,2l-diol-3,20-dione 2l-acetate 9u-chloro-l 1fi-thiol-16a-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 21-acetate 9 ot-chloro-1 lli-thiomethyl ether-16 a-methyl- 1,4-p regnadiene-l7a,2l-diol-3,20-dione fill-acetate 9DL-ChlO1'O-1 lfi-thiophenyl ether-l 6a-methyl-l ,4-pregnadiene-17a,21-diol-3,20-dione 21-acetate, respectively.

The starting steroids for our process can be any 90:- halogeno steroid which is also substituted at 0-11 by a. sulfonyloxy radical such as disclosed hereinabove or a halogen, provided that when there is a 9a-iodo group at C9, the halogen at Cll is other than iodo, i.e. is a 11fi-fluoro-, llfi-chloroor llfi-bromo. Usually, our starting compounds are 9a-halogeno-11flsubstituted steroids of the androstane and pregnane series including l9-nor analogs thereof. Many of these compounds are known and, if not readily available, are conveniently prepared from the corresponding 9(11)-dehydro steroid according to known procedures such as described (in the case of 9a,11 8-dihalogeno steroids) in US. Patents Nos. 2,894,963; 3,009,927; 3,009,033; 3,009,938; 3,026,339; 3,032,564; 3,049,554 and 3,131,200. The 9ct-halogenollfl-sulfonyloxy starting steroids are also prepared via procedures known in the art (and as described in detail in Example 8A) from the corresponding 9(11)-dehydro steroid by reaction with p-toluene sulfonic acid in pyri dine together with N-bromosuccinimide or N-chlorosuecinimide, for example, whereby are prepared the corresponding 9a-bromo-ll 8-tosyloxy and the 90t-Ch1OIO-11/3- tosyloxy steroid, respectively. Some typical intermediates of this group are 9et-chloro-1 lfip-toluenesulfonyloxy-1,4-pregnadienel7a,21-diol-3,20-dione 21-cathylate,

9a-chloro-l 1,8-tosyloxyl ,4-androstadienel 7B-ol-3-one,

9 x-chloro-11,8-tosyloxy-19-nor-4-androstene-3,17-dione.

When the above 9ot-chloro-115-tosyloxy steroids are treated with water in methanol at, for example 60 C., the tosyloxy group at C-ll is replaced by hydroxy and there are obtained the corresponding 9a-halogeno-11/ihydroxy derivatives, i.e. 9a-chloro-1lfl-hydroxy-lA-pregnadiene-l7ot,21-diol-3,20-dione in admixture with the 21- cathylate thereof, 9u-chloro-1IB-hydroxy-1,4-androsta- 7 diene-17fl-ol-3-one and 9a-ch1oro-11B-hydroxy-19-nor-4- androstene-3,17-dione, respectively.

Typical 9,11-dihalogcno steroids which undergo the process of this invention include 9,1l-dihalogeno-androstanes such as:

9oz,1 lfi-dichloro-1,4-androstadiene-3,17-dione,

9oc,1 1 8-dich1orol7u-methyl-testosterone acetate,

9a-bromo-11,B-fluoro-l,4 androstadiene-3,17-dione,

9a-iodo-1LS-chloro-1,4-androstadiene-3,17-dione,

9'oc-Chl0r0-1 1,8-fiuoro-1,4-androstadiene17,8-ol-3-one l7-propionate,

9a-br0mo-1 1B-fluoro-1,4-androstadiene-17fi-ol-3-one 17-propionate,

each of which when heated with Water in methanol at about 60 C. for at least two days will yield the corresponding 9a-halogen0-11;3-hydroxy androstane possessing androgenic activity, e.g.

9a-chloro-1 1/3-hydroxy-1,4-androstadiene-3,17-dione,

9a-ChlOI'0-1 IB-hydroxy-17u-methy1-testosterone acetate,

9ot-bromo-1l/B-hydroxy-1,4-androstadiene-3 ,17-dione,

9a-iOdO-1 1/3-hydroxy-1,4androstadiene-3 l7-dione,

9u-chloro-1 lfi-hydroxy-1,4-androstadiene-17,8-ol-3-one 17-propionate,

9u-bromo-1 1 B-hydroxy-1,4-androstadiene- 17 3-01-3 -one 17-propionate, respectively.

Other 90:,11fi-dihfl10g6110 starting steroids include 90c, 1lfi-dihalogeno-19-nor-androstanes such as:

6cc,-fl1101'0-9oc, 1 1 fl-dichloro-19-nor-4-androsten- 3,17-dione, and 9a-bromo-11fl-chloro-19 nor-4-androsten,3, 17-dione when treated with water in methanol at 60 C. yields:

6oc-fluOIO-9oz-ChlOrO-1 1 fl-hydroxy-19-nor-4-androsten 3 ,17-dione, and 9u-bromo-1 IB-hydroxy-19-nor-4-androsten-3,17 dine,

respectively, valuable as anabolic and androgenic agents. Included among the 9a,11;8-dihalogeno progesterones which may be used in our process are such as:

9:1,1 1 B-dichloro- 17 a-hydroxy-progesterone,

90:1 1 B-dichloroprogesterone,

9 (1,1 l fi-dichloro- 17 a-acetoxyprogesterone,

9u-chloro-1 1B-fluoro-1,4-pregnadiene-3 ,20-dione,

9ot,1 1fi-dichloro-19-norprogesterone and 9u-bromo-1 1 p-fluoro 17 a-hydroxy-19-norpro gesterone.

Each of the foregoing, upon treatment with water in methanol at 60 C. according to our process yields:

9a-chloro-11,8,17a-dihydroxy-progesterone, 9a-chloro-1 1 B-hydroxyprogesterone,

9a-chloro-1 1fl-hydroxy-17a-acetoxyprogesterone, 9oc-ChlOl'O-1 lfl-hydroxy-1,4-pregnadiene-3 ,20-dione, 9a-chloro-l ly8-hydroxy-19-norprogesterone and 9a-bromo-11,8,17a-dihydroxy-l9-norprogesterone,

respectively, valuable as progestational and anti-conception agents.

Of particular value as starting compounds for the preferred mode of our process are the 21-oxygenated- 9,11-diha1ogenopregnanes such as are described in US. Patents Nos, 2,894,963 and 3,049,554, including 901,115- dichloro-1,4-pregnadiene-17a,21-diol3,20-dione, the 16oz methyland the 165-methyl homoloks thereof as well as the 2l-lower alkanoate and 21-disodium phosphate esters thereof, each of which when treated with water according to our process yields the corresponding 9u-chlorollfi-hydroxy-pregnane, e.g. 9a-chloro-prednisolone, the 160L-1T1thy1 and the 16fi-ho-mologs thereof as well as their 21-lower alkanoates and 21-disodium phosphate esters thereof, all of which are known valuable antiinflammatory agents.

For purposes of illustration, the process of this invention is disclosed in detail below. It is to be understood that the examples are merely illustrative of the process and are not to be construed as limiting the invention. Obvious equivalents, including those set forth above will be apparent to one skilled in the art.

PREPARATION A Preparation of 9u-bromo 11/3 chloro-16m-methyl-L4- pregnadiene-17a,21 diol 3,20 dione 21 disodium phosphate (1) 16a-methyl 1,4,9 (11) pregnatriene-17a,2l-diol- 3,20-dione.To a solution of 20.6 g. of 16a-methyl- 1,4,9 l1)-pregnatriene-17u,21 -diol-3,20-dione 21-cathylate in 150 ml. of tetrahydrofurane, ml. of methanol and 50 ml. of water at 0 C., add drop-wise 50 ml, of l-Normal aqueous sodium hydroxide over a one-hour period with stirring while bubbling nitrogen through the solution. Continue stirring at 0 C. under a blanket of nitrogen for another hour and one-half, then neutralize with acetic acid.

Pour into water and filter the resultant precipitate comprising 16a methyl-1,4,9(ll)-pregnatriene-l7ot,2ldiol-3,20-dione.

(2) 16a methyl 1,4,9(11) pregnatriene-17u,21- diol-3,20-dione ZI-methanesulfonate-To a solution of 16 g. of 16a-methyl-1,4,9(11)-pregnatriene-17a,21-diol- 3,20-dione in 160 ml. of pyridine at 0 C., with stirring add drop-wise over a 30-minute period 16 ml. of methanesulfonyl chloride, stir at 0 C. for 30 minutes then pour into dilute aqueous hydrochloric acid, filter the resultant precipitate, wash with water and air dry to give 16amethyl-1,4,9'(11)-pregnatriene 1701,21 diol-3,20-dione 2 l-meth ane sulfonate.

Purify by recrystallizing fromqacetone-hexane.

(3) 16a methyl 21 iodo-1,4,9(11)-pregnatriene- 17a01-3,20-di0118.-T0 12 g. of 16u-methyl-1,4,9(11)- pregnatriene-17a,21-diol-3,20-dione 21-methanesulfonate in 180 ml. of acetone, add 12 g. of sodium iodide and reflux the reaction mixture for 15 minutes. Pour into water and filter, wash with water and dry the resultant precipitate comprising 16m methyl 21 iodo-1,4,9 (11)- pregnatriene-17a-ol-3,20-dione.

(4) 16oz methyl 1,4,9(11) pregnatriene-17a,2ldiol-3,20-dione 21-phosphate.To 43.03 ml. of methanol at room temperature, add drop-wise with stirring 24.40 m1. of 85% phosphoric acid. To this add cautiously 75.40 ml. of triethylamine followed by 12.7 g. of l6a-methyl-21- iodo-1,4,9(1 1 -pregnatriene-17a-ol-3 ,20-dione. Warm the reaction mixture on a steam bath for 30 \minutes, then with stirring pour into water (260 ml.) containing concentrated hydrochloric acid (72.54 m1.)

Filter the resultant precipitate comprising l6a-methyl- 1,4,9(11) pregnatriene-17a,2l-diol-3,20 dione 21-phosphate. Purify by crystallization from aqueous acetone.

(5 9a bromo-ll li-chloro-16ot-methyl-1,4-pregnadiene- 17a,2l-diol-3,20-dione 21-phosphate.-To a solution of 3.27 g. of 160: methyl-l,4,9(11)-pregnatriene-17a,21- diol-3,20-dione 21-phosphate in ml. of glacial acetic acid, add 13.05 g, of lithium chloride and 1.13 g. of N- bromo acetamide followed immediately by 315 mg. of lithium chloride in tetrahydrofurane (1.35 ml.). Allow the solution to warm to room temperature, then stir for 1 hour and 15 minutes. Pour into water and acidify with concentrated hydrochloric acid.

Filter and dry the resultant precipitate comprising 9ot-bromo 11,6 chloro 16ot-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 21-phosphate. Purify by crystallization from acetone-hexane, M.P. C. dec.; [ab +116.8 (dioxane).

(6) 9a bromo 11B chloro-16oz methyl 1,4- pregnadiene-17a,21-diol-3,20 dione 21-disodium phosphate.- -To a solution of 2 g. of 9ot-bromo-l1B-chloroa methyl-l,4-pregnadiene-l7u,2l-diol, 3,20 dione 21-phosphate in 100 ml. of aqueous methanol (1:3), add

with stirring aqueous sodium hydroxide until the solution is :at pH 9.5.

Pour the reaction mixture into 600 m1. of acetone and filter and air dry the resultant precipitate comprising 9u-bromo-1lB-chloro-16a methyl 1,4 pregnadiene- 17u,2l-diol-3,20-dione 2l-disodium phosphate.

EXAMPLE 1 9u-chloro-1 lfi-hydroxyd 6u-methyl-1,4-pregnadiene-17u, 2l-diol-3,20-dione (9ot-chol0-16ot-methylpre-dnisolene) A. Preparation of 9a-chloro-11,8-hydroxy-l6a-methyl- 1,4 pregnadiene 17a,21 diol 3,20 dione 21 phosphate from 90:,11/3-di6h10f0 16a methyl 1,4 pregnadiene 17oc,21 diol 3,20 dione 21 disodium phosphate by treatment with water: (1) Heat a solution of 9cc,1 1 8 dichloro 16a methyl 1,4 pregnadiene 17a,- 21 diol 3,20 dione 21 disodium phosphate (800 mg.) in 40 ml. of distilled Water at 60 C. for six hours (pH 5.6). Acidity the reaction mixture to a pH less than one by adding hydrochloric acid, and filter the resultant precipitate comprising 9a chloro 11,8 hydroxy 16amethyl 1,4 pregnadiene 1711,21 diol 3,20 dione 21-phosphate (400 mg). Purify by recrystallization from acetone-water, M.P. 173-175.1 C. [a] +106 (dioxane).

(2) In a manner similar to the described above, treat each of 9ot,11fi dichloro 16,6 methyl 1,4 pregnadiene 17a,21 diol 3,30 dione 21 disodium phosphate and 9a,11 3 dichloro 1,4 pregnadiene 17u,21- diol 3,20 dione 21 disodium phosphate with water at 60 C. for six hours. Isolate and purify the resultant products produced thereby in the described manner to obtain, respectively, 90: chloro 11/8 hydroxy 165- methyl 1,4 pregnadiene 17ot,21 diol 3,20 dione 21 phosphate and 90a chloro 11,8 hydroxy 1,4- pregnadiene 17ot,21 diol 3,20 dione 21 phosphate.

Similarly, by utilizing 9u,1lfl-dichlorol pregnene- 17a,21-diol-3,20-dione 21-disodium phosphate as the starting compound in the above procedure, there is obtained 9oz chloro 113 hydroxy 4 pregnene 170:,- 21 diol 3,20 dione 21 phosphate (i.e. 9a chlorohydrocortisone 21-phosphate), active as an anti-inflammatory agent.

B. 90: chloro 11B hydroxy 16oz methyl 1,4- pregnadiene 17a,21 diol 3,20 dione: (1) To 300 mg. of 90a chloro 11/3 hydroxy 16a methyl 1,4- pregnadiene 17a,21 diol 3,20 dione 21 phosphate dissolved in 4.0 ml. of a 1 molar aqueous trishydroxymethylaminomethane solution titrated to pH 8 with bydrochloric acid add 0.2 ml. of bacterial alkaline phosphatase (Worthington Biochemical Corporation, Freehold, N.J.-chromatographically purified grade). Maintain the reaction mixture at 37 C. for 20 minutes, cool to 25 C., add Water, and filter the resultant precipitate comprising 90c chloro 11B hydroxy 16a methyl 1,4 pregnadiene 170;,21 diol 3,20 dione. Purify by thin layer chromatography utilizing as solvent chloroform-ethyl acetate (1:1). From the preparative plate, extract the more polar product with chloroform-ethyl acetate (1:1). Concentrate the ethyl acetate-chloroform extract and recrystallize the resultant residue from acetone/ hexane; M.P.

237-238" C. (dec.); +1069 (dimethylformamide);

(2) In similar manner, treat 9u-chloro-11B-hydroxy- 161i methyl 1,4 pregnadiene 170:,21 diol 3,20- dione 21-phosphate with bacterial alkaline phosphatase in aqueous trishydroxymethylaminomethane. Isolate and purify the resultant products in a manner similar to that described to obtain 9a chloro 115 hydroxy 16/3- methyl 1,4 pregnadiene 1706,21 diol 3,20 dione (i.e. 90: chloro 16,8 methylprednisolone).

(3) Similarly, treat 9a-chloro-hydrocortisone 21phos phate with bacterial alkaline phosphatase as described above to obtain 9ot-chlorohydrocortisone.

(4) In a manner similar to that described in above Procedure 1B(1), treat chloro 11B hydroxy- 1,4 pregnadiene 170:,21 diol 3,20 dione 21 phosphate with bacterial alkaline phosphatase. Isolate the resultant product in a manner similar to the described in 1B(1) to give 90c chloro 1113 hydroxy 1,4 pregnadiene 17a,21 diol 3,20 dione (i.e. 90c chloroprednisolone).

Dissolve mg. of 9a-chloroprednisolone (prepared as in the preceding paragraph) in pyridine (1.5 ml.) with acetic anhydride (0.15) and allow to stand at room temperature for 18 hours. Pour into water and filter, wash with Water, and dry the resultant precipitate comprising 9a-chloroprednisolone 21-acetate. Purify by silica gel preparative thin-layer chromatography utilizing chloroformethyl acetate (3:2) as solvent. Extract the more polar product from the preparative plate with methylene chloride and tetrahydrofuran. Crystallize from acetone-hexane yielding 9a-chloroprednisolone Zl-acetate, M.P. 229- 235 C. (dec.) [a] +141 (ethanol);

ggihnnnl 239 mlu =14,700)

EXAMPLE 2 Preparation of 9a-chloro-1lp-hydroxy-16ot-methyl-1,4- pregnadiene 1704,21 diol 3,20 dione 21 phosphate from 904,115 dichloro 16a methyl 1,4- pregnadiene 17a,21 diol 3,20 dione 21 --disodium phosphate by treatment with Water methanol (50:50)

In a manner similar to that described in Example 1A, heat a solution of 500 mg. 911,1I/B-dichloro-lM-methyl- 1,4 pregnadiene 17u,21 diol 3,20 dione 21 disodium phosphate in 40 ml. of a methanol water mixture (50:50) at 60 C. for 24 hours. Acidify the reaction mixture to a pH less than one by adding hydrochloric acid. Filter the resultant precipitate comprising 9u-chl0ro-11fihydroxy 16oz methyl 1,4 pregnadiene 1704,21 diol- 3,20 dione 21 phosphate. Purify by crystallization from acetone/hexane, M.P. 173-175 C.

EXAMPLE 3 9a-chloro-l lfl-hydroxy-16a-methyl-1,4-pregnadiene-17a, 2 l-diol-3 ,20'dione (9u-chloro- 1 6ot-methylprednisolone) A. Preparation of 90a chloro 11,8hydroxy 16mmethyl 1,4 pregnadiene :,21 diol 3,20 dione 21-diol-3,20-dione (9a-chloro-16a-methylprednisolone) 1,4 pregnadiene 17a,21 diol 3,20 dione 21 disodium phosphate by treatment with human scrum. Dissolve 800 mg. of 16ot-methyl-9oc,11,B-dichloro-1,4- pregnadiene-17a,21-diol-3,20dione 21-disodium phosphate in 40 ml. of human serum (human whole blood less red cells) at pH 7. Stir the reaction mixture at 38 C. for five days, then add water. Add concentrated hydrochloric acid until the pH of the reaction mixture is less than one, then extract with ethyl acetate (about one liter). Wash the combined ethyl acetate extracts With water, then dry over sodium sulfate and evaporate in vacuo to a residue comprising 90c chloro 11,3 hydroxy 16oz methyl- 1,4 pregnadiene 170:,21 diol 3,20 dione 21 phosphate (460 mg). This product Was used Without purification in procedure 3B immediately following.

Similarly, when the above reaction is carried out for only 24 hours at 38 C. (rather than for five days as set forth above) and the resultant product is isolated and purified in a manner similar to that described above, there is obtained 90c chloro 11,8 hydroxy 16amethyl 1,4 pregnacliene 17a,21 diol 3,20 dione 21-phosphate.

B. 9a ChlOIO-16oc-I11thY1Pf6dIliSOlOI16.-TO 300 mg. of the product of Example 3A comprising 9ot-c'hloro-16amethylprednisolone 2l-phosphate dissolved in 6 m1. of a one molar aqueous solution of trishydroxymethylaminomethane titrate to pH 8 with hydrochloric acid, add 0.3

ml. of bacterial alkaline phosphatase. Maintain the reaction mixture at 37 C. for 20 minutes. Add water and extract With methylene chloride. Combine the methylene chloride extracts, wash with water, dry over sodium sulfate, and evaporate to a residue (224 mg.) comprising 90:- chloro-llfl-hydroxy-16a-methyl-1,4-pregnadiene 170:,21- diol-3,20-dione. Purify by thin layer chromatography utilizing as solvent chloroform-ethyl acetate (3 :2). From the preparative plate, extract the more polar product with methylene chloride-acetone. Concentrate the methylene chloride acetone extract and crystallize the resultant residue from acetone-hexane to give 9a-chloro-11fl-hydroxy- 16a-methyl-1,4-pregn-adiene-l7o,2l-diol-3,20-dione.

EXAMPLE 4 Preparation of 9a-chloro-11B,17u-dihydroxyprogesterone from 9oc,l 1B dichloro 17a hydroxyprogesterone by treatment with water-methanol (1: l)

Dissolve 115 mg. of 9a,11/3-dichloro-17a-hydroxyprogesterone in methanol (400 ml.) and water (400 ml.). Heat the solution with stirring at 60 C. for 24 hours. Distill the reaction mixture to a smaller volume, then add water and extract with methylene chloride. Evaporate the combined methylene chloride extracts to a residue comprising 9a-chloro-115,17a-dihydroxyprogesterone. Purify by thin layer chromatography utilizing a solvent chloroform ethyl acetate (3:1). From the preparative plate, extract the more polar solvent product with chloroform-acetone. Concentrate the combined extracts and crystallize the resultant residue from ether to give 9ot-chloro- 1 1,9,17a-dihydroxyprogesterone;

A$) 240 mp; A213? 2.87, 5.87, 602, and 616p EXAMPLE 5 9a bromo 115 chloro 16a-methyl-1,4 pregnadiene- 17a,21-dl0l3,20-di0fl6 (9ot-bromo-16a-methylprednisolone) A. Preparation of 9a-bromo-11/8-hydroxy-16u-methyl- 1,4-pregnadiene-17a,21-diol-3,2l-dione 2l-phosphate from 90: bromo 11B chloro l6a-methyl-l,4 pregnadiene l7u,2l-diol-3,20-dione 21-disodium phosphate by treatment with water.dissolved 9oz-bIOII10-ll/i-ChlOIO-l6ctmethyl-1,4-pregnadiene-l7a,2l diol-3,20-dione 2l-disodium phosphate (800 mg.) in distilled water (40 ml.) and stir at 60 C. for three hours, cool, (solution pH=2) and acidity the reaction mixture to a pH less than one by adding hydrochloric acid. Extract the reaction mixture with ethyl acetate. Dry the combined extracts over sodium sulfate, and evaporate in vacuo to a residue (560 mg.) comprising 9a-bromo-1 lB-hydroxy-l6a-methyl-l,4-pregnadiene-17a,21-diol-3,20-dione 2l-phosphate. This product is used without further purification in following Procedure 5B.

B. 9a-bromo-1lfi-hydroxy-lM-methyl 1,4 pregnadiene-l7a,21-diol-3,20-dione.-Dissolve 5 60 mg. of 9abromo-1l/3-hydroxy-16a methyl-1,4-pregnadiene-17a,21- diol-3,20-dione 21-phosphate (prepared as in Example 5A) in 12 ml. of one molar aqueous trishydroxymethylaminomethane titrate to pH 8 with hydrochloric acid. Add 0.5 ml. of macterial alkaline phosphatase, and maintain the reaction mixture at 37 C. for 20 minutes. Add water to the reaction mixture, extract with chloroform, dry the combined extracts over sodium sulfate, and evaporate to a residue comprising 9a-bromo-ll 8-hydroxy-l6a-methyl- 1,4-pregnadiene-17a,2l-diol-3,20-dione (323 mg). Purify by thin layer chromatography utilizing as solvent chloroform ethyl acetate (3:2). From the preparative plate, extract the more polar product with methylene chloride-acetone (1:1) and evaporate the extract to a residue comprising 9a-bromo-l1/3-hydroxy-16a-methyl-1,4 pregnadiene-17a,21-diol-3,20-dione.

EXAMPLE 6 9,8,1lfi-oxido-l6ot-methyl-1,4-pregnadiene-17u,2l-

diol-3 ,20-dione 2.95, 5.78, 6.00, 6.17, 6.3 and 11.2 2

EXAMPLE 7 Preparation of 9a-chloro-llfi-hydroxy-l6a-methyl-l,4- pregnadiene-l7a,2l-diol-3,20-dione 21-acetate (9a-chloro-l6a-methyl-prednisolone 21-acetate) from 912,11 .8- dichloro-16u-methyl 1,4-pregnadiene-17a,21-diol-3,20- dione 21-acetate by treatment with water-methanol max.

A. Dissolve 9u-11/3 dichloro 16a-methyl 1,4 pregnadiene 170:,21 diol 3,20-dione 21-acetate mg.) in methanol (400 ml.) and water (400 ml.) and stir at 60 C. for 24 hours. Concentrate the reaction mixture in vacuo until it is about one-third its original volume. Filter, and extract the aqueous filtrate with methylene chloride. Dry the combined methylene chloride extracts over sodium Sulfate and evaporate to a residue comprising a mixture of 9a chloro 1113 hydroxy-16u-methyl-1,4-pregnadienel7a,2l-dio1-3,20-dione and the 21-acetlate thereof.

Dissolve the above product mixture in pyridine (0.4 ml.), and add acetic anhydride (0.04 ml.), and allow to stand at room temperature for about 18 hours. Pour into water, extract with ethyl acetate. Combine the ethyl acetate extracts, wash with water, dry over sodium sulfate, filter, and evaporate to a residue comprising Qua-chloro- 11,8-hydroxy-16a-methyl-1,4-pregnadiene 170:,21 diol- 3,20-dione 21-acetate (9ot-chloro-16a-methylprednisolone Zl-acetate). Purify by thin layer chromatography utilizing chloroform-ethyl acetate (3:2) as solvent. Extract the more polar product from the preparative plate with acetone and methylene chloride. Evaporate this extract to a residue and crystallize from acetone-hexane. The infrared spectrum matches that of an authentic sample of 9oc-Chl0- ro-l6a-methylprednisolone 2l-acetone as follows;

2.86, 2.95, 5.64, 5.8, 6.0, 6.14., 6.20 and 11.22,.

B. Stir a solution of 90:,11fl dichloro-16a-methyl-L4- pregnadiene-17a,21-diol-3,20-dione ZI-acetate (200 mg.) in methanol (40 ml.) plus distilled water (20 ml.) at 60 C. for four days. Add a large volume of water and filter. Wash with water, and dry the resultant precipitate comprising 900 chloro-11B hydroxy-16m methyl-1,4- pregnadiene 17u,21-dio1-3,20-dione and the 2l-acetate thereof, as well as some starting material (158 mg). Isolate the desired product by thin layer chromatography utilizing chloroform-ethyl acetate (3:2) as solvent. Extract the more polar products from the preparative plate with acetone-methylene chloride, and evaporate this extract to a residue comprising a mixture of 9a-chloro-11B- hydroxy 160a methyl 1,4-pregnadiene 17a,21-diol- 3,20-dione and the 21-acetate thereof. Dissolve this product mixture in pyridine (1.6 ml.). Add acetic anhydride (0.6 ml.) and allow to stand at room temperature for about 18 hours. Pour into water, and filter. Wash with water, and dry the resultant product comprising 911- chloro-11fi-hydroxy-16a-methyl 1,4-pregnadiene 17a, 21-di01-3,20-dione ZI-acetate. Purify by thin layer chromatography utilizing chloroform-ethyl acetate (3:2) as solvent and extracting the more polar product with acemax.

tone-methylene chloride to obtain 9a-chloro-16a-methylprednisolone ZI-acetate.

C. In above procedures 7A and 7B, by utilizing instead of 90:,11B-dl6hl010 l6a-methyl-1,4-pregnadiene- 17a,21-diOl-3,20 dione 21-acetate, other 9a,1lp-dihalogeno steroids such as 9a,11fl dichloro 4-pregnene- 16a,17a,21 triol-3,20-dione 16,21-diacetate, Zea-methyl- 9a11fi dichloro-4-pregnene 17n-21-diol 3,20-dione 21- acetate, there is obtained, respectively 9a-Chl0l0 115- hydroxy-4-pregnene-16a,17a,21-triol 3,20-dione 16,21-diacetate in admixture with the 16-mono-acetate thereof, and 20a methyl 9a-chloro llfi-hydroxy 4 pregneue- 17u,21-diol3,20-dione in admixture with the 21-acetate thereof.

Reaction of each of the foregoing with acetic anhydride in pyridine will yield the respective completely esterified product.

D. In above procedure 7A and 7B, lower alkanoic I acid esters may be present at C-21 such as the 21-tbutyrate, 2l-enanthate, 21-caproate, 21-caprylate, and 21- decanoate of 9a,ll[i-dichl0ro 16ot-methy1 1,4-pregnadiene-17u,21-diol-3,20-dione, and there will be prepared 9oc-Chl0IO-l1fl hydroxy 16a-methyl-1,4 pregnadiene- 17a,21-diol-3,20-di0ne in admixture with the corresponding 21-alkanoate.

EXAMPLE 8 9a-chloro llfi-hydroxy 16amethyl 1,4-pregnadiene- 17a,21-diOl-3,2O dione 21 cathylate (9ot-ChlOI0-16ocmethylprednisolone ZI-cathylate) A. 9a-chloro llp-tosyloxy 16ot-methyl-1,4-pregnadiene-17,21-diol 3,20-dione 21-cathylate.-The requisite intermediate 16a-methyl-1,4,9(11)-pregnatriene 17a,21- diol-3,20-dione 21-cathylate is prepared from lu-methyl-1,4,9(11) pregnatriene 17u,21 diol 3,20-dione utilizing known procedures by treatment with ethylchloro carbonate in pyridine at room temperature.

Dissolve 100 g. of p-toluene sulfonic acid monohydrate and 27.33 g. of sodium p-toluene sulfonate in one liter of pyridine and concentrate this solution in vacuo to about 500 ml. maintaining the temperature at about 40 C. Cool to room temperature and add 13.17 g. of recrystallized N-chlorosuccini-mide followed immediately with 20 g. of l6a-methyl l,4,9(11)-pregnatriene-17a21-diol- 3,20-dione 21-cathylate (prepared as described above). Stir the reaction mixture at room temperature for 20 hours, then pour into 10 liters of an ice/water mixture containing one liter of concentrated sulfuric acid. Filter the resultant precipitate, wash to neutrality with water and air dry at 60 C. to give 9ot-chloro-1lfl-tosyloxy-16otmethyl 1,4-pregnadiene-17a,2l-diol-3,20-dione 21-cathylate. Purify by chromatography on silica gel eluting with l15% ethyl acetate in chloroform. Combine the early, like fractions and concentrate to a residue. Crystallize this residue from acetone-hexane to give 9achloro-llB-tosyloxy 16ot-methyl-1,4 pregnadiene-l7a, 2l-diol 3,20-di0ne 21-cathylate; M.P. 201-203 C.; [a] +65 (dioxane);

B. Preparation of 9a-chloro-11B-hydroxy 16ot-methyl- 1,4-pregnadiene 17a,21-diol-3,20-di0ne 21 cathylate (9oz-Chl0l0 16a-methylprednisolone 2l-cathylate) from 9a-chloro llfl-tosyloxy 16u-methyl-1,4-pregnadiene- 17oc,21 diol-3,20-dione ZI-cathylate by treatment with methanol-water (1:1).Heat a solution of 9a-chlorollfi-tosyloxy 1a-methyl-1,4-pregnadiene 17oz,21-di0l- 3,20-dione ZI-cathylate (100 mg.) in methanol (400 ml.) and distilled water (400 ml.) at 60 C. for 24 hours. Concentrate the reaction mixture to a volume of about 20 ml. Cool and filter the resultant product comprising 906' chloro llfi-hydroxy 16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20 dione 21-cathylate. Purify by thin layer chromatography on a preparative thin layer plate (silica gel) utilizing ethyl acetate-chloroform (1:3) as solvent followed by crystallization from acetone-hexane; M.P. 214-219 C. Yield=55 mg.

In the preceding paragraph, the infrared spectrum and the thin layer chromatography of this compound is identical to that of a sample prepared according to the alternate procedure described in Example 8C below.

C. Dissolve mg. of 9tx-ehloro 16a-methylprednisolone in 1 ml. of dry pyridine at 0-5 C. Add 0.03 ml. of ethyl chloroformate and stir at 0-5 C. for one hour. Pour the reaction mixture into 10 ml. of water containing 1 ml. of hydrochloric acid. Filter and dry the re sultant precipitate comprising 9a-chloro-16a-methylprednisolone 21-cathylate.

EXAMPLE 9 Preparation of 9a-chloro llp-azido 16a-methyl-1,4-

pregnadiene 17u,21'diol-3,20-dione 21-cathylate from 9a-chloro 11,8-tosyloxy 16ot-methyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 2l-cathylate by treatment with sodium azide in methanol-water (1:1)

Add acetic acid to a solution of g. of sodium azide in 1.5 liters of water and 1.5 liters of methanol until the pH of the solution is 6.6. Add 3 g. of 9oc-Cl1lOIO-11B- tosyloxy 16a-methyl'1,4-pregnadiene 17a,21-diol-3,20- dione 21-c-athylate and stir at 60 C. for 48 hours. Add 2 liters of water and extract with methylene chloride. Wash the combined methylene chloride extracts with water and dry over magesium sulfate. Concentrate in vacuo to a residue comprising 9oz chloro-llflazido 16a-methyl 1,4-pregnadiene 17a,21-di0l-3,20- dione 21-cathylate. Purify via preparative thin layer chromatography on silica gel utilizing ethyl acetatecyclohexane (2:3) as solvent followed by crystallization from acetone-hexane to give 9u-chloro-11,9-azido 16wmethyl-l,4 pregnadiene 17a,21-diO1-3,20 dione 21- cathylate; M.P. 220-223 C.; [a] |168.4 (diox-ane);

Preparation of 911,115 dichloro-l6u-methyl-L4-pregnadiene 17a,21-diol-3,20-dione 21-cathylate from 9achloro llfl-tosyloxy 16a-methy1 1,4-pregnadienel7a,21-diol-3,20-dione 21 cathylate by treatment with sodium chloride in methanol-water (1:1)

To a solution of 40 g. of sodium chloride in 200 ml. of methanol and 200 ml. of Water, add 50 mg. of 9a-chlorollfl-tosyloxy 1a-methyl-1,4-pregnadiene 17a,21-dio1- 3,20-dione 21-cathylate (the compound of Example 8A), and heat at 60 C. for 70 hours. Concentrate the reaction mixture almost to dryness, then add methylene chloride and filter. Dry the methylene chloride solution over magnesium sulfate and concentrate to a residue comprising 9a,11/3-dichloro 16a-methyl 1,4-pregnadiene 17a, 21-dio1-3,20-dione 21-cathylate.

EXAMPLE 11 9a-chloro-11,6-azido-16wmethyl-1,4-pregnadiene- 17a,21-diol-3,20-dione 21-acetate A. 9a-chloro Il s-tosyloxy 16a-methy1-1,4-pregnadiene-17u,21-diol-3,20-dione 21-acetate.--To a solution of 16a-methyl 1,4,9(11) pregnatriene 17a,21-dio1-3, 20-dione 21-acetate (6.0 g.) in 600 ml. of pyridine, add 8 g. of sodium tosylate and 30 g. of p-toluene sulfonic acid monohydrate. Concentrate the mixture to a volume of 300 ml., then add 4 g. of N-chlorosuccinimide and stir at room temperature for 24 hours. Pour the reaction mixture into 3 liters of cold 10% aqueous sulfuric acid. Filter and air dry the resultant precipitate comprising 9a chloro llfi-tosyloxy 16oz methyl 1,4-pregnadiene- 17a,21-diol-3,20:-dione ZI-acetate. Purify via chromatography on silica gel eluting with 15% ethyl acetate in chloroform. Evaporate the combined eluates to a residue,

then crystallize the residue from acetone-hexanej M.P. 203206 C.; [u] +71.2 (dioxane);

xggthanol B. Preparation of 9a-chloro llfi-azido 16a-methyl- 1,4-pregnadiene 17a,21-diol-3,20-dione 21-acetate from 9a-chloro llfl-tosyloxy 16a-methyl 1,4-pregnadiene- 17a,21 diol 2,20-dione 2l-acetate by treatment with methanol-water.To a solution of 100 g. of sodium azide in one liter of water and 2.5 liters of methanol, add acetic acid until the solution is at pH 6.0. Add 2 g. of 9achloro llfl-tosyloxy 16a-methyl 1,4 pregnadiene- 17ot,21-diOl-3,20-di0116 2l-acetate and stir at 60 C. for 24 hours. Add 3 liters of water to the reaction mixture and extract with methylene chloride. Wash the methylene chloride extracts with water, dry over magnesium sulfate and concentrate to a residue comprising 9achloro llfi-azido 16a-methyl 1,4-pregnadiene 17oz, 2l-diol-3,20-dione 21-acetate. Purify via preparative thin layer chromatography on silica gel utilizing as solvent ethyl acetate-cyclohexane (2:3). Extract with chloroform the chloro-azide product as determined by infrared and ultraviolet spectra, then recrystallize the residue of the chloroform extracts from ethyl acetate; M.P. 246247 C.; [a] +l77.8 (dioxane);

mg? 238 l EXAMPLE 12 Preparation of 9a-chloro llfi-hydroxy 17u-methyl-4- androsten 17fi-ol-3-one from 9a,11,B-dichloro 17amethyl-4-androsten 17,8-ol-3-0ne by treatment with water-methanol Heat a solution of 100 mg. of 9a,11fi-dichloro 17ozmethyl-4-androsten 17B-ol-3-one in 400 ml. of methanol and 400 ml. distilled water at 60 C. for 48 hours. Concentrate the reaction mixture in vacuo to about 20 ml., then extract the residue with methylene chloride. Dry the methylene chloride extract with anhydrous magnesium sulfate and concentrate in vacuo to a residue comprising 9a chloro 11B hydroxy 17a-11'16thY1-4- androsten l7j3-ol-3-one (i.e. 9a-Chl010 llfi-hydroxy- 17cc methyltestosterone). Purify vi-a preparative thinlayer chromatography on silica gel eluting with chloroform ethyl acetate (9:1). Crystallize from acetonehexane.

EXAMPLE 13 Preparation of 6oc-fl110f0 9oz-Chl010 11fi-hydroxy-19- nor-4-androstne 3,17-dione from 6a-fluoro-9a,11p-dichloro-19-nor-4-androstene 3,17 dione by treatment with water-methanol In a manner similar to that described in Example 12, heat 100 mg. of 6a-fiuoro-9a,11B dichloro 19-nor-4- androstene 3,17-dione in 400 ml. of water and 400 ml. of methanol for 72 hours at 60 C. Isolate and purify the resultant product in a manner similar to that described in Example 12 to give 6a-fluoro-9u-chloro 11,8-hydroxy- 19-nor-4-androstene-3,l7-dione.

EXAMPLE 14 Preparation of 9a chloro 11,3 hydroxy 19 nor-4- pregnene-3,20-dione (9a-chloro llfi-hydroxy-lQ-norprogesterone) from 9a,11;8 dichloro 19 nor 4- pregnene-3,20-dione by treatment with water-methanol Heat 100 mg. of 9a,1l}8 dichloro-19-nor-4-pregnene- 3,20-dione in 400 ml. of distilled water and 400 ml. of methanol at 60 C. for 48 hours. Isolate and purify the resultant product in a manner described in Example 12 to get 90: chloro llp-hydroxy 19-nor-4-pregnene-3,20- dione.

16 EXAMPLE 1s 9u-chloro-11/3-hydroxy-1,4-androstadien-17fl-ol-3-one A. chloro 1lp-tosyloxy-1,4-androstadien-17 3-01-3- one.Dissolve 40 gm. of p-toluene sulfonic acid monohydrate and 7 gm. of sodium p-toluene sulfonate in 600 ml. of pyridine. Then concentrate the solution in vacuo to about 300 ml. At room temperature add 3 gm. of 1,4,9 (ll)-androstatrien-17/3-ol-3-one followed immediately by 2.8 gm. of recrystallized N-chlorosuccinimide. Stir the reaction mixture at room temperature for 20 hours, then pour into 4 liters of iced water containing 400 ml. of concentrated sulfuric acid. Filter, wash to neutrality with water and air dry at 60 C., the resultant precipitate comprising 9a chloro-l lB-tosyloxy-l,4-androstadien-175-01-3- one. Purify via chromatography on silica gel, eluting with 10:15% ethyl acetate in chloroform. Concentrate the combined eluants and crystallize the resultant residue from acetone-hexane.

B. Preparation of 9a-chloro-1lfi-hydroxy-lA-androstadien-17p-o1-3-one from 9a-chloro-1lfl-tosyloxy-lA-androstadien-l7fl-ol-3-one by treatment with water-methanol. Heat a solution of mg. of 9a-chloro-1lfi-tosyloxy-IA- androstadien-l7/i-ol-3-one in 400 ml. of distilled water and 400 ml. methanol at 60 C. for 24 hours. Isolate and purify the resultant product in a manner similar to that described in Example 12 to give 9a-chloro-11fl-hydroxy- 1,4-androstadien-l7fi-ol-3-one.

EXAMPLE l6 9a-ch1oro-1 lfi-hydroxyl9-nor-4-androstene-3, l7-dione A. 90c chloro-1lfl-tosyloxy-l9-nor-4-androstene-3,17- dione.Dissolve 70 g. of p-toluene sulfonic acid monohydrate and 19 g. of sodium p-toluene sulfonate in 1 liter of pyridine, then concentrate the solution to a volume of 500 ml. Add 5 g. of l9-nor-4,9(11)-androstadiene-3,l7- dione followed immediately by 5 g. of recrystallized N- chlorosuccinimide and stir at room temperature for 18 hours. Pour the reaction mixture into 4 liters of iced water containing 400 ml. of concentrated sulfuric acid. Filter the resultant precipitate, wash to neutrality with water and air dry to yield 9a-chloro-1lfi-tosyloxy-l9-nor-4-androstene-3,17-dione. Purify via chromatography on silica gel eluting with 10: 15% ethyl acetate in chloroform. Concentrate the combined eluants and crystallize the resultant residue from acetone-hexane.

B. Preparation of 9a-chloro-11fl-hydroxy-19-nor-4-androstene-3,17-dione from 9a-chloro-1l/i-tosyloxy-l9-nor- 4-androstene-3,17-dione.-Stir'a solution of 100 mg. of 9c:- chloro-l lfi-tosyloxy-19-nor-4-androstene-3,l7-dione in 400 ml. of methanol and 400 ml. of water at 60 C. -for 24 hours. Isolate the resultant product in a manner similar to that described in Example 12 to give 9a-chloro-l1/3- hydroxy-19-nor-4-androstene-3,17-dione.

EXAMPLE l7 90z-ChlOI'O-l 1 3-17 a-dihydroxy-19-nor-progesterone A. 90c chloro-l1B-tosyloxy-17a-hydroxy-19-nor-progesterone.In a manner similar to that described in Example 15A, dissolve 48 g. of p-toluene sulfonic acid monohydrate and 9.7 g. of sodium p-toluene sulfonate in 600 ml. pyridine and concentrate the solution in vacuo to a volume of 400 ml. Add 4 g. of 17a-hydroxy-l9-nor-4,9(11) progesterone followed immediately by 3.4 g. of recrystallized N-chlorosuccinimide. Stir at room temperature for 18 hours. Isolate and purify the resultant product in a manner similar to that described in Example 15A to give 9ozchloro-l lfl-tosyloxy-17a-hydroxy-l9-progesterone.

B. Preparation of 91x. chloro-1 1(3-17 a-dihydroxy-19-norprogesterone from 9a-chloro-11/3-tosyloxy-17a-hydroxy- 19-nor-progesterone.Stir a solution of 100 mg. of 9c:- chloro 1lfl-tosyloxy-lh-hydroxy-l9-nor-progesterone in 400 ml. of methanol and 400 ml. of water at 60 C. for 24 hours. Isolate and purify the resultant product in a manner similar to that described in Example 12 to give 9a-chloro-11(3-17u-dihydroxy-l9-nor-progesterone.

EXAMPLE 18 9a-chloro-1lfi-hydroxy-lGee-methyl-1,4-pregnadiene-17a, 21 -diol-3,20-dione 2 l-alkoxycarboxylates A. In a manner similar to that described in Example 8, other 2l-alkoxycarboxyloxy esters of 16-methyl-l,4,9(ll)- pregnatriene-l7u,2l-diol-3,20-dione are prepared by treatment thereof with other alkylchlorocarbonates such as methylchlorocarbonate, propylchlorocarbonate, n-butylchlorocarbonate, n-octylchlorocarbonate, and n-decylchlorocarbonate to obtain respectively, the 2l-carbornethoxylate, 2l-carbopropoxylate, 21-carbobutoxylate, 21-carbooctoxylate and the 2l-carbodecoxalate of 16 xmethyl-1,4, 9(11)-pregnatriene-17a,21-diol-3,20-dione.

Treat each of the foregoing 2l-carboalkoxylates with ptoluene sulfonic acid and the sodium salt thereof in the manner described in Example 8A. Isolate and purify the resultant products in the manner described to obtain, respectively, the 2l-carbomethoxylate, 21-carbopropoxylate, 2l-carbobutoxylate, 21-carbo-octoxylate and 21-carbodecoxylate, respectively of 9a chloro-l1B-tosyloxy-16amethyl-1,4-pregnadiene-17a,2l-diol-3,20-dione.

B. Treat each of the 9a-chloro-1lB-tosyloxy-pregnadiene-ZLcarboalkoxylates prepared in the foregoing example with aqueous methanol at 60 C. in a manner similar to that described in Example 8B. Isolate and purify the resultant products in a manner similar to that described to obtain, respectively the ZI-carbomethoxylate, 2l-carbopropoxylate, 21-carbobutoxylate, 21-carbo-octoxylate and 21-carbodecoxylate, respectively of 9a chloro-llfi-hydroxy-l6a-methyl-1,4-pregnadiene-17u,2l-di0l-3,20-dione.

We claim:

1. The process which comprises reacting a 9a-ha1ogeno- 11fl-X-steroid selected from the group consisting of the androstane and preganane series and the 19-nor-analogs thereof, wherein X is a member selected from the group consisting of a halogeno, hydrocarbonsulfonyloxy having up to 20 carbon atoms, and substituted hydrocarbonsulfonyloxy having up to 20 carbon atoms, X being other than iodowhen said 9a-halogenois 9a-i0do,

with a reagent defined by the formula: YZ,

wherein Y is an anion selected from the group consisting of hydroxyl, azide and halide;

and Z is a cation selected from the group consisting of hydrogen, ammonium, alkali metal ions, and alkaline earth metal ions;

whereby is elfected replacement of said llli-X group by said anion Y, and there is formed a 9a-halogenollfi-Y-steroid selected from the group consisting of the androstane and preganane series and the l9-nor analogs thereof, Y being as hereinabove defined.

2. The process according to claim 1 when carried out in a hydroxylic solvent, said process comprising reacting a 9a-halogeno-1LB-X-steroid selected from the group consisting of the androstane and pregnane series and the 19- nor-analogs thereof, wherein X is a member selected from the group consisting of halogeno, hydrocarbonsulfonyloxy having up to 20 carbon atoms, and substituted hydrocarbonsulfonyloxy having up to 20 carbon atoms, X being other than iodo when said 9u-halogenois 90:- iodo-;

in a hydroxylic solvent with a reagent defined by the formula, YZ:

wherein Y is an anion selected from the group consisting of hydroxyl, azide and halide;

and Z is a cation selected from the group consisting of hydrogen, ammonium, alkali metal ions, and alkaline earth metal ions;

whereby is effected replacement of said llfi-X-group by said anion Y, and there is formed a 9a-halogenollfi-Y-steroid, Y being as hereinabove defined.

3. The process of claim 1 when carried out in the presence of water.

4. The process of claim 2 when carried out in the presence of water.

5. The process of claim 2 wherein said hydroxylic solvent is aqueous methanol.

6. The process of claim 2 wherein said 9u-halogenoll-fl-X steroid is a 9a-halogeno-ll-fi-X-pregnane substituted at C-2l by a member selected from the group consisting of hydroxy, alkanoyloxy having up to 10 carbon atoms, alkoxycarbonyloxy having up to 10 carbon atoms, and phosphate alkali metal salt;

whereby is formed a 9u-halogeno-llfl-Y-pregnane substituted at 0-21 by a member selected from the group consisting of hydroxy, alkanoyloxy having up to 10 carbon atoms, alkoxycarbonyloxy having up to 10 carbon atoms, and phosphate alkali metal salt, Y being as defined in claim 2.

7. The process according to claim 1 wherein said 904- halogeno-l l/8-X-steroid is a 9a-halogeno-llB-chloro-4- pregnene-17a, 21-diol-3,20-dione 2l-phosphate sodium salt; and said reagent, YZ, is water (Y being hydroxyl and Z being hydrogen);

whereby is effected replacement of said 11,B-chloro group by said hydroxyl and there is formed a 9mhalogeno 11,8-hydroxy-4-pregnene-17a,21-diol-3,20- dione 2l-ph0sphate sodium salt.

8. A process according to claim 7 wherein said 9ahalogeno llfl chloro-4pregnene-l7a,2l-diol-3,20-dione 21-phosphate sodium salt is 9a-1lfl-dichloro-l6a-methyl- 1,4-pregnadiene-17a,2l-diol-3,20-dione 2l-disodium phosphate;

said process comprising reacting 9a,11/3-dichlOr0-16amethyl 1,4-pregnadiene-l7u,2l-diol-3,20-dione 21- disodium phosphate with water;

whereby is formed 9a-chlor0-11fi-hydroxy-16a-methyl- 1,4 pregnadiene-17a,21-diol-3,20-dione 21-sodium phosphate.

9. A process according to claim 7 wherein said 9ahalogeno 1113-chloro-4-pregnene-l7a,21-diol-3,20-dione Ill-phosphate sodium salt is 9a,llfi-dichloro-lofi-methyl- 1,4-pregnadiene-17a,21-diol-3,20-dione 21disodium phosphate;

said process comprising reacting 9a,11 3-dichloro-16B- methyl-1,4-pregnadiene-l70,2 l-diol-3,20-dione 2l-disodium phosphate with water;

whereby is formed 9a-chloro-1lfi-hydroxy-IGB-methyl- 1,4 pregnadiene-17a,21-diol-3,20-dione ZO-sodium phosphate. 10. A process according to claim 7 wherein said 911- halogeno 11/3 chloro-4-pregnene-l7a,2l-diol-3,20-dione 21-phosphate sodium salt is 9u-bromo-l1p-ch1oro-16amethyl 1,4pregnadiene-17a,21-diol-3,20-dione 21-disodiurn phosphate;

said process comprising reacting said 9a-br0m0-1lflchloro 16a methyl-1,4-pregnariiene-17a,2l-diol-3, ZO-dione 21-disodium phosphate with water;

whereby is formed 9w'bromo-11/3-hydroxy-l6a-methyl- 1,4 pregnadiene-17a,21-diol-3,20-dione 21-sodium phosphate.

11. A process according to claim 1 wherein said halogeno-llB-X-steroid is a member selected from the group consisting of a 9a-chloro-11B-tosyloxy-4-pregnene- 17a,21-diol-3,20-dione and the 21-lower alkanoates and 21-alkoxycarboxylates thereof having up to 10 carbon atoms,

and wherein YZ is water (Y being hydroxyl and Z being hydrogen);

whereby is formed a 9a-halogen0-1lfl-hydroxy-steroid selected from the group consisting of a 9a-Chl010- 1 1fl-hydroxy-4-pregnene-17,21-diol-3,20-dione and the 21-lower alkanoate and the 2l-alkoxycarboxylate thereof.

12. A process according to claim .2 wherein said 90:- halogeno-llfi-X-steroid is a member selected from the group consisting of a 9a-chloro-1lfi-tosyloxyt-pregnene- 17a,21-dio1-3,20-dione 21-lower alkanoate and a 901- 19 chloro-l lfl-tosyloxyi-pregnene-17u-21-diol-3,20-dione 21- alkoxycarboxylate, and wherein said hydroxylic solvent is aqueous methanol;

whereby is effected replacement of said llfl-tosyloxy group by said anion Y (Y being as defined in claim 2), and there is formed a member selected from the group consisting of a 9a-chloro-11B-Y-4-pregnene-l7a,21-diol-3,20-dione 21-lower alkanoate and a 9a chloro-l1B-Y-4-pregnene-17a,21-di0l-3,20-dione 2l-alkoxycarboxylate. 13. A process according to claim 2 wherein said reagent, YZ, is water (Y being hydroxyl and Z being hydrogen), said hydroxylic solvent is methanol, and said 9a-halogeno-1lfi-X-steroid is a member selected from the group consisting of 9u-chloro-11B-tosyloXy-16a-methyll,4-pregnadiene-17a,2l-diol-3,20-dione ZI-cathylate and 90: chloro-11 3-tosyloxy-16a-methyl-1,4-pregnadiene17a, 21-diol-3,20-dione ZI-acetate;

said process comprising reacting a member selected from the group consisting of 9a-chloro-lll8-tosyloxy- 16a methyl-1,4-pregnadiene-17a,21-diol-3,20-dione 21-cathylate and 9a-chloro-1lfl-tosyloxy-l6a-methyl- 1,4 pregnadiene-17a,21-diol-3,20-dione 2l-acetate with water in methanol;

whereby is effected replacement of said llfl-tosyloxy group by said hydroxyl, and there is formed a member selected from the group consisting of 9oc-Ch10l'0- 11B hydroxy 16a-methyl-l,4-pregnadiene-l7a,21- diol-3,20-dione 2l-cathylate and 9a-chloro-11fi-hydroxy 16a-methyl-1,4-pregnadiene-17a,21-di0l-3,20 dione 21-acetate.

14. A process according to claim 12 wherein said 900- halogeno-llfl-X-steroid is a member selected from the group consisting of 9a-chloro-11/3-tosyloxy-16u-methyl- 17a,21-diol-3,20-dione ZI-acetate and 9a-Ch10l'O-11B- tosyloxy 16a, methyl-1,4-pregnadiene-l7a,21-diol-3,20-

dione 21-cathy1ate, and said reagent, YZ, is sodium azide (Y being azido, Z being sodium ion);

said process comprising reacting a member selected from the group consisting of 9a-chloro-11fl-tosyloxy- 16a methyl-1,4-pregnadiene-17a,21-dio1-3,20-dione 21-acetate and 9a-chloro llfi-tosyloxy-l6a,methyl- 1,4-pregnadiene-17a,21-diol-3,20-dione 21-cathylate with sodium azide in aqueous methanol;

whereby is formed a member selected from the group consisting of 9c: chloro-11B-azido-16a-methyl-L4- pregnadiene-17a,21-diol-3,20-dione 21-acetate and 9a chloro 1lfi-azido-16a-methyl-1,4-pregnadienel7a,2l-diol-3,20-dione 21-cathylate.

15. A process according to claim 12 wherein said reagent, YZ, is sodium chloride (Y being chloride and Z being sodium ion), and

said 9u-halogeno-1 1 8- -steroid is 9a-Ch10lO-1lfi-tOSY1- oxy 16a methyl-1,4-pregnadiene-17a,21-di01-3,20- dione 21-cathylate which comprises reacting 9achloro 115 tosyloxy-1Ga-methyI-IA-pregnadiene- 17a,21-diol-3,20-dione 21-cathylate with sodium chloride in aqueous methanol;

whereby is formed 901,1lfi-dichloro-l6u-methyl-l,4-

pregnadiene-17a,21-diol-3,20-dione ZI-cathylate.

References Cited UNITED STATES PATENTS 7/1959 Gould et a1. 260397.45 8/1962 Gould et a1. 260397.45

LEWIS GOTTS, Primary Examiner E. G. LOVE, Assistant Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,463,793 August 26, 196

Hershel L. Herzog et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, lines 18 and 19, cancel "(preferably anion".

Column 2, line 31, "Orangic" should read Organic Colum1 3, line 65 "set set forth" should read set forth Colul 4, line 13, "thta" should read that line 22, after "sodium phosphate" insert and 9 +fluoro-llB-hydroxyl,4- pregnadienel7a,Zl-diol-3,ZO-dione 21-sodium phosphate Column 5, line 10, "9a-cholor-" should read 9a-chloro- Column 6, line 5, "well be" should read will be Column 7, line 65, "homoloks" should read homologs Column 8,

lines 46 and 47, "24.40 ml." should read 24.05 ml. C011 9, line 11, "(Qcx-cholo-l6u-methylprednisolene)" should read [9a-chloro-l6a-methylprednisolone) line 27, "to the" shoulc' read to that line 29, "3,30-dione" should read -3,2( dione Column 10, line 7, "to the" should read to that lines 48 and 49 should read Zl-phosphate from 9a,lle

dichloro-l6amethyl-1,4-pregnadiene-l7a,2l-diol3,20-dione 21- diline 75, "titrate" should read titrated Column 11, line 34, "602" should read 6 02 line 37, "11B- chloro" should read 11Bhydroxy line 42, "3,2l--dione" should read 3,20-dione line 46, "water. dissolved" should read water.-Dissolve Column 11, line 63, "titrate" should read titrated line 64, "macterial" shou read bacterial Column 15, line 51, "4androstne-" shoul read 4-androstene- Column 17, line 15, "2lcarbode coxalate" should read 2l-carbodecoxylate Column 18, line 46, "3,20-dione 20-sodium" should read 3,20-dione 21- sodium Signed and sealed this 5th day of May 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. Attesting Officer WILLIAM E. SCHUYLER, JR Commissioner of Patents 

